CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203341Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`
`****Pre-decisional Agency Information****
`
`
`
`
`
`Memorandum
`
`Date:
`September 4, 2012
`
`
`To:
`
`
`
`
`From:
`
`
`
`Dianne Hanner – Regulatory Project Manager
`Division of Hematology Products (DHP)
`
`Richard Lyght, Pharm.D. – Regulatory Review Officer
`Division of Direct to Consumer Promotion (DCDP)
`Office of Prescription Drug Promotion (OPDP)
`
`
`Subject:
`
`OPDP comments on draft Bolsulif (bosutinib) tablets, for oral use
`Patient Information (PPI)
`
`
`
`
`
`
`
`
`This consult is in response to DHP’s January 6, 2012 request for OPDP review of
`the draft Bolsulif Patient Information. DCDP comments are based on the
`proposed draft marked-up labeling submitted by Pfizer on August 31, 2012.
`
`We have made no comments at this time.
`
`OPDP appreciates the opportunity to provide comments. If you have any
`questions, please contact Richard Lyght at 301-796-2874 or at
`richard.lyght@fda.hhs.gov.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3184035
`
`1
`
`7 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RICHARD A LYGHT
`09/04/2012
`
`Reference ID: 3184035
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`Division of Professional Drug Promotion
`
`****Pre-decisional Agency Information****
`
`
`
`
`
`9/4/2012
`
`Memorandum
`
`Date:
`
`
`To:
`
`
`
`
`From:
`
`
`
`Diane Hanner, Senior Program Manager
`Division of Hematology Products
`
`James Dvorsky, Regulatory Reviewer
`Division of Professional Drug Promotion
`
`
`
`
`Subject:
`
`Comments on draft labeling (Package Insert) for NDA 203341, Bosulif (bosutinib)
`tablets
`
`
`
`
`
`
`
`
`In response to your labeling consult request on January 6, 2012, we have reviewed the draft
`Package Insert for Bosulif and do not have any comments. Note that this review was based
`upon the August 30, 2012 version of the label.
`
`
`Reference ID: 3183833
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JAMES S DVORSKY
`09/04/2012
`
`Reference ID: 3183833
`
`

`

`Division of Hematology Products
`
`REGULATORY PROJECT MANAGER LABELING REVIEW
`
`
`Application: NDA 203341
`
`Name of Drug: BOSULIF® (bosutinib) Tablets, 100 mg and 500 mg.
`
`
`Applicant: Wyeth Pharmaceuticals, Inc.
`
`
`Labeling Reviewed
`
`
`Submission Date: November 17, 2011
`
`
`Receipt Date: November 17, 2011
`
`
`
`Background and Summary Description:
`
`This new drug application provides for the use of BOSULIF® (bosutinib) Tablets, 100 mg and
`500 mg for the treatment of adult patients with chronic, accelerated, or blast phase Ph+ chronic
`myelogenous leukemia (CML) with resistance, or intolerance to prior therapy
`
`
`Review
`NDA 203341 bosutinib label was reviewed by the DHP RPM staff which made several proposed
`formatting changes.
`
`
`Regulatory Project Manager
`
`Chief, Project Management Staff
`
`Recommendations
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Date
`
`Date
`
`
`
`1
`
`Reference ID: 3183991
`
`32 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this
`page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DIANE C HANNER
`09/04/2012
`
`JANET K JAMISON
`09/04/2012
`
`Reference ID: 3183991
`
`

`

`PMR/PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`PMR Description:
`
`Conduct a drug-drug interaction trial to evaluate the effect of a
`moderate CYP3A4 inhibitor (e.g. erythromycin) on the
`pharmacokinetics of bosutinib. The proposed protocol must be
`submitted for review and concurrence prior to trial initiation.
`
`
`
`Final protocol Submission Date:
`Study/Clinical trial Completion Date:
`Final Report Submission Date:
`
`
`03/17/2013
`09/17/2014
`03/17/2015
`
`
`PMR/PMC Schedule Milestones:
`
`
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`Ketoconazole (strong CYP3A4 inhibitor) increased bosutinib Cmax 5-fold and AUC 9-fold
`in a dedicated drug interaction trial. A moderate CYP3A4 inhibitor will likely cause increased
`exposures as well and a dose adjustment may be needed in patients on concomitant moderate
`CYP3A4 inhibitors. No clinical drug-drug interaction trial has been conducted with moderate
`CYP3A4 inhibitors. Therefore, a drug interaction trial with a moderate CYP3A inhibitor, such as
`erythromycin, is required.
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`
`
`
`
`The co-administration of bosutinib with a moderate CYP3A4 inhibitor will likely result in increased
`exposure of bosutinib. Increased bosutinib exposure would likely result in increases in toxicities
`such as diarrhea, thrombocytopenia and rash. This trial will allow the identification of a dose of
`bosutinib that could safely be co-administered with moderate CYP3A inhibitors. Moderate CYP3A4
`inhibitors include some commonly used drugs such as fluconazole, erythromycin, diltiazem,
`verapamil and ciprofloxacin.
`
`
`1
`
`
`
`Reference ID: 3183395
`
`

`

`
`
`
`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`
`
`
`
`
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`
`
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`The required drug-drug interaction trial will likely be a crossover trial to evaluate the effect of a
`moderate CYP3A4 inhibitor on the pharmacokinetics of bosutinib.
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
`Continuation of Question 4
`
`
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
`
`
`
`Reference ID: 3183395
`
`2
`
`
`
`

`

` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
`
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`
`PMR/PMC Development Coordinator:
`This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the
`safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality.
`
`RCK____________________________
`(signature line for BLAs)
`
`
`
`Reference ID: 3183395
`
`3
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DIANE C HANNER
`08/31/2012
`
`ROBERT C KANE
`09/04/2012
`
`Reference ID: 3183395
`
`

`

`PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`NDA #/Product Name:
`
`PMC Description:
`
`Bosulif (bosutinib)
`
`The Applicant agrees to continue to follow patients (on treatment and
`in protocol defined post-treatment follow-up) enrolled in
`Study 200-WW at least an additional 2 years past the March
`28, 2011 cut-off date. The Final Report will consist of an
`updated report containing, at a minimum, data through
`March 28, 2013.
`
`
`
`Final Protocol Submission:
`Trial Completion:
`Final Report Submission:
`Other:
`
`
` NA
` N/A
` 12/2015
` NA
`
`
`
`PMC Schedule Milestones:
`
`
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`At the time of database lock, the median duration of follow-up for the primary efficacy population
`of patients with second-line CML who were imatinib-resistant was 30.5 months (range: 0.7 to 58
`months). Many of the median durations of response had not been reached. The median durations of
`response would be an important additional piece of information for prescribers. The safety and
`efficacy of bosutinib over a longer time period will enhance understanding of the drug and its use in
`patients with CML.
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`PMR/PMC Development Template
`
`Last Updated 8/31/2012
`
`Page 1 of 4
`
`Reference ID: 3183402
`
`

`

`Extended follow-up of ongoing trial will enhance knowledge of the safety profile and will enhance
`knowledge of duration of efficacy.
`
`
`
`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`
`
`
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`This PMC refers to continuation of the ongoing pivotal trial, Trial 200-WW which is a single arm,
`multi-center trial of oral daily dosing of 500 mg of bosutinib for patients with chronic phase,
`accelerated phase and blast phase CML.
`
`PMR/PMC Development Template
`
`Last Updated 8/31/2012
`
`Page 2 of 4
`
`Reference ID: 3183402
`
`

`

`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Continuation of Question 4
`
`
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`
`PMR/PMC Development Coordinator:
` This PMC has been reviewed for clarity and consistency, and is necessary to further refine the
`safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality.
`
`
`___RCK__________
`(signature line for BLAs)
`
`
`
`PMR/PMC Development Template
`
`Last Updated 8/31/2012
`
`Page 3 of 4
`
`Reference ID: 3183402
`
`

`

`Reviewer, DO YOU WANT TO REQUEST THE SPONSOR TO:
`
`F S
`
`ubmit the protocol for FDA review and concurrence before commencing the trial? No
`
`PMR/PMC Development Template
`
`Last Updated 8/31/2012
`
`Page 4 of4
`
`Reference ID: 3183402
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DIANE C HANNER
`08/31/2012
`
`ROBERT C KANE
`09/04/2012
`
`Reference ID: 3183402
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Medical Policy Initiatives
`Division of Medical Policy Programs
`
`PATIENT LABELING REVIEW
`
`August 24, 2012
`
`Ann Farell, MD
`Director
`Division of Hematology Products (DHP)
`
`LaShawn Griffiths, MSHS-PH, BSN, RN
`Associate Director for Patient Labeling
`Division of Medical Policy Programs (DMPP)
`Barbara Fuller, RN, MSN, CWOCN
`Team Leader, Patient Labeling
`Division of Medical Policy Programs (DMPP)
`
`Latonia M. Ford, RN, BSN, MBA
`Patient Labeling Reviewer
`Division of Medical Policy Programs (DMPP)
`
`DMPP Review of Patient Labeling: Patient Package Insert
`(PPI)
`
`BOSULIF (bosutinib)
`
`tablets for oral use
`
`203341
`
`Wyeth Pharmaceuticals, Inc.
`
`Date:
`
`To:
`
`Through:
`
`From:
`
`Subject:
`
`
`Drug Name (established
`name):
`Dosage Form and Route:
`
`Application
`Type/Number:
`Applicant:
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3180101
`
`
`
`

`

`1
`
`
`
`INTRODUCTION
`On November 17, 2011, Wyeth Pharmaceuticals, Inc. submitted an Original New
`Drug Application (NDA) 203341 under section 505(b) of the Federal Food, Drug and
`Cosmetic Act, for BOSULIF (bosutinib) tablets. The Applicant’s proposed indication
`for BOSULIF (bosutinib) tablets is for the treatment of chronic, accelerated, or blast
`phase Ph+ chronic myelogenous leukemia (CML) in adult patients with resistance or
`intolerance to prior therapy.
`On November 18, 2011, the Division of Hematology Products (DHP) requested that
`the Division of Medical Policy Programs (DMPP) review the Applicant’s proposed
`Patient Package Insert (PPI) for BOSULIF (bosutinib) tablets.
`This review is written in response to a request by Division of Hematology Products
`(DHP) for Division of Medical Policy Programs (DMPP) to review the Applicant’s
`proposed Patient Package Insert (PPI) for BOSULIF (bosutinib) tablets.
`
`
` 2
`
` MATERIAL REVIEWED
`• Draft BOSULIF (bosutinib) tablets Patient Package Insert (PPI) received on
`November 17, 2011, revised by the Review Division throughout the review cycle,
`and received by DMPP on August 22, 2012.
`• Draft BOSULIF (bosutinib) tablets Prescribing Information (PI) received on
`November 17, 2011, revised by the Review Division throughout the review cycle,
`and received by DMPP on August 22, 2012.
`• Approved Sprycel (dasatinib) comparator labeling dated October 7, 2011.
`
`3 REVIEW METHODS
`To enhance patient comprehension, materials should be written at a 6th to 8th grade
`reading level, and have a reading ease score of at least 60%. A reading ease score of
`60% corresponds to an 8th grade reading level. In our review of the PPI the target
`reading level is at or below an 8th grade level.
`Additionally, in 2008 the American Society of Consultant Pharmacists Foundation
`(ASCP) in collaboration with the American Foundation for the Blind (AFB)
`published Guidelines for Prescription Labeling and Consumer Medication
`Information for People with Vision Loss. The ASCP and AFB recommended using
`fonts such as Verdana, Arial or APHont to make medical information more
`accessible for patients with vision loss. We have reformatted the PPI document
`using the Verdana font, size 11.
`In our review of the PPI we have:
`•
`simplified wording and clarified concepts where possible
`•
`ensured that the PPI is consistent with the Prescribing Information (PI)
`•
`removed unnecessary or redundant information
`
`
`
`
`
`Reference ID: 3180101
`
`
`
`

`

`•
`
`•
`
`ensured that the PPI meets the criteria as specified in FDA’s Guidance for
`Useful Written Consumer Medication Information (published July 2006)
`ensured that the PPI is consistent with the approved comparator labeling where
`applicable.
`
` CONCLUSIONS
`The PPI is acceptable with our recommended changes.
`
` 4
`
` 5
`
` RECOMMENDATIONS
`• Please send these comments to the Applicant and copy DMPP on the
`correspondence.
`• Our review of the PPI is appended to this memorandum. Consult DMPP
`regarding any additional revisions made to the PI to determine if corresponding
`revisions need to be made to the PPI.
` Please let us know if you have any questions.
`
`
`
`
`
`
`Reference ID: 3180101
`
`
`
`10 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this
`page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LATONIA M FORD
`08/28/2012
`
`BARBARA A FULLER
`08/28/2012
`
`LASHAWN M GRIFFITHS
`08/28/2012
`
`Reference ID: 3180101
`
`

`

`Executive CAC
`Date of Meeting: July 17, 2012
`
`Committee: David Jacobson-Kram, Ph.D., OND IO, Chair
`Abby Jacobs, Ph.D., OND IO, Member
`Paul Brown, Ph.D., OND IO, Member
`Haleh Saber, Ph.D., DHOT, Supervisor and Alternate Member
`Shawna Weis, Ph.D., DHOT, Presenting Reviewer
`
`
`Author of Draft:
`Shawna Weis
`The following information reflects a brief summary of the Committee discussion
`and its recommendations.
`NDA #203341
`Drug Name: Bosutinib
`Sponsor: Wyeth (Pfizer)
`Background:
`Bosutinib is an Abl and Src kinase inhibitor that is undergoing development for Ph(+)
`CML in adult patients with resistance or intolerance to prior therapy. Bosutinib was
`negative in the Ames and in vitro chromosome aberration assays, both with and without
`activation by Arochlor-induced S9 extracts. Bosutinib was also negative in the in vivo
`micronucleus assay in rats. A protocol (SPA) and supporting toxicity data were
`submitted to the CAC for the 2-year rat study in June of 2009, and concurrence was
`obtained on dose selection for this study. All males were terminated during Week 91 due
`to excessive mortality. Females were terminated during Week 100.
`
`Rat Carcinogenicity Study
`Sprague-Dawley rats were dosed daily by oral gavage in a 10 mL/kg dose volume. Doses
`were 0 (water), 0 (vehicle), 0 (vehicle), 1.5, 5, and 15 mg/kg/day for females and 0
`(water), 0 (vehicle), 0 (vehicle), 2.5, 7.5, and 25/15 mg/kg/day for males. Due to the
`large number of deaths, doses were reduced for males in the high dose cohort during
`Study Week 78, and then suspended during Study Week 79 until termination in Study
`Week 86.
`Each dose group consisted of 60 males and 60 females, plus an appropriate number of
`toxicokinetic satellite cohorts to permit confirmation of exposure and toxicokinetic
`assessment on Study Day 182. Doses were administered by gavage in a vehicle
`suspension (0.5% carboxymethylcellulose 2% polysorbate 80, and 0.06% glacial acetic
`acid). Three control groups, (two vehicle and one water group), were employed in this
`study.
`This study was relocated from the Sponsor facility in Chazy, NY to the CRO site in
`
`
`
`Reference ID: 3160756
`
`(b)
`(4)
`
`

`

`during week 36 of dosing.
`Plasma exposure levels achieved in this study were up to 1.5-3-fold (AUCτ) greater than
`those anticipated clinically at the 500 mg/day dose level.
`
`Executive CAC Recommendations and Conclusions (Rat):
`• The Committee agreed that the study was acceptable, but noted that moving an
`ongoing carcinogenicity study is undesirable and rendered historical control data
`difficult to interpret due to numerous differences between the two sites.
`• The Committee concurred that the study was negative for drug-induced
`neoplasms.
`
`David Jacobson-Kram, Ph.D.
`Chair, Executive CAC
`
`
`cc:\
`/Division File, NDA 203341; DHP
`/Haleh Saber; DHOT
`/Shawna Weis, DHOT
`/Diane Hanner, CSO/PM, DHP
`/Adele Seifried, OND IO
`
`
`
`Reference ID: 3160756
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ADELE S SEIFRIED
`07/18/2012
`
`DAVID JACOBSON KRAM
`07/18/2012
`
`Reference ID: 3160756
`
`

`

`
`
`M E M O R A N D U M
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
` PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
` ____________________________________________________________________________________________
`
`
`
`
`
`
`
`DATE:
`
`TO:
`
`
`
`
`
`
`
`FROM:
`
`
`
`
`
`CLINICAL INSPECTION SUMMARY
`
`June 28, 2012
`
`Diane Hanner, Regulatory Project Manager
`Karen McGinn, M.S.N., C.R.N.P., Clinical Analyst
`Virginia Kwitkowski, M.S., R.N., A.C.N.P.-B.C., Team Leader
`Division of Hematology Products (DHP)
`
`Anthony Orencia, M.D., F.A.C.P.
`Medical Officer, GCP Assessment Branch
`Division of Good Clinical Practice Compliance
`Office of Scientific Investigations
`
`
`THROUGH: Janice Pohlman, M.D., M.P.H.
`
`
`Team Leader, GCP Assessment Branch
`Division of Good Clinical Practice Compliance
`Office of Scientific Investigations
`
`
`
`
`
`
`Susan D. Thompson, M.D.
`Acting Branch Chief, GCP Assessment Branch
`Division of Good Clinical Practice Compliance
`Office of Scientific Investigations
`
`203341
`
`
`
`
`
`
`
`SUBJECT: Evaluation of Clinical Inspections
`
`NDA:
`
`APPLICANT: Wyeth Pharmaceuticals, Inc.
`
`bosutinib
`DRUG:
`Yes
`NME:
`THERAPEUTIC CLASSIFICATION/REVIEW: Standard Review
`
`INDICATION: adult chronic myelogenous leukemia
`
`CONSULTATION REQUEST DATE:
`INSPECTION UMMARY GOAL DATE:
`DIVISION ACTION GOAL DATE:
`PDUFA DATE:
`
`February 9, 2012 (Signed)
`July 2, 2012
`September 17, 2012
`September 17, 2012
`
`
`
`
`
`Reference ID: 3151958
`
`

`

`Page 2 NDA 203341 bosutinib
`Clinical Inspection Summary
`
`I. BACKGROUND:
`
`The most common phenotype of Philadelphia chromosome positive leukemia is chronic
`myelogenous leukemia (CML), which is most frequently associated with a 210 kD BCR-
`Abl fusion protein. BCR-Abl is a transcript resulting from the 9:22 chromosomal
`translocation responsible for formation of the Philadelphia (Ph) chromosome. This fusion
`protein (BCR-Abl), with constitutive tyrosine kinase activity, consists of the breakpoint
`cluster region (BCR) and Abelson kinase (Abl). Bosutinib is an orally bioavailable
`inhibitor of both Src-family and Abl kinases. Unlike imatinib, dasatinib and nilotinib,
`bosutinib exhibits no significant inhibition of c-kit or PDGFR proteins.
`
` A
`
` single adequate study was submitted in support of this NDA. Two U.S. clinical sites
`were selected for clinical audit. A brief summary of the submitted study is given below.
`
`Protocol 3160A4-200-WW
`
`Protocol 3160A4-200-WW was an open-labeled, continuous daily dosing, Phase I and II
`safety and efficacy study of bosutinib in patients with Philadelphia chromosome positive
`(Ph+) leukemias. Phase I was a dose-escalation study in chronic phase CML subjects to
`establish the maximum tolerated drug dose in this subject population [Part 1]. Study
`3160A4-200-WW [Part 2] was a safety and efficacy study of 500 mg daily bosutinib in
`chronic phase, imatinib resistant/refractory CML subjects, and subjects with advanced
`Philadelphia chromosome positive leukemia. The primary objective was to determine the
`proportion of patients attaining a major cytogenetic response with imatinib-resistant
`chronic phase CML, who have no prior Src, Abl, or Src-Abl kinase inhibitor exposure
`other than imatinib, and to determine the population pharmacokinetic parameters of
`bosutinib. DHP directed OSI to focus on the Phase II clinical efficacy and safety aspects
`of this NDA in the clinical site audits.
`
`Efficacy was defined primarily via analysis of peripheral blood and bone marrow
`findings. The efficacy endpoints constituted (1) major cytogenetic response for CML
`subjects in their chronic phase and (2) hematologic response for advanced Ph+ leukemia
`subjects (i.e., in the accelerated or blast phase). A cytogenetic response at 24 weeks for
`chronic CML subjects was defined as a complete plus a partial cytogenetic molecular
`response to treatment. Quantitatively, this was based on a log reduction from baseline in
`the BCR-Abl/Abl ratio. A partial cytogenetic response was defined as less than three log
`reduction from baseline in the BCR-Abl/Abl ratio. A major cytogenetic response was
`defined as a three or greater log reduction from standardized baseline in the BCR-
`Abl/Abl ratio. A complete cytogenetic response was defined as an undetectable BCR-Abl
`fusion protein. A complete hematologic response for advanced Ph+ patients was
`defined as (i) bone marrow blast percentage value of 5 or less, (ii) platelet count over
`100,000 or 100 x 109/L, (iii) total white blood cells within the clinical site’s upper limit of
`normal, (iv) absolute neutrophil count over 1,000 or 1.0 x 109/L, (v) basophil count less
`than 20%, (vi) absence of other significant findings such as promyelocytes or blasts in the
`peripheral blood, and (vii) absence of extramedullary involvement.
`
`
`
`Reference ID: 3151958
`
`

`

`Page 3 NDA 203341 bosutinib
`Clinical Inspection Summary
`
`Protocol/Study Site
`
`Insp. Date
`
`May 9 to 18, 2012
`
`Final
`Classification*
`Preliminary:
`NAI
`
`
`II. RESULTS:
`
`Name of CI
`City, State
`Jorge Cortes,
`M.D.
`Houston, TX
`Hanna Khoury,
`M.D.
`Atlanta, GA
`Wyeth
`Pharmaceuticals,
`Inc.
`Groton, CT
`
`*Key to Classifications
`NAI = No deviation from regulations. Data acceptable.
`VAI-No Response Requested = Deviations(s) from regulations. Data acceptable.
`VAI-Response Requested = Deviation(s) from regulations. See specific comments be